We have found that the treatment of immature thymocytes with anti-CD8 antibodies under cross-linking conditionsinduces rapid apoptosis. Treatment of the thymocytes with the phorbol ester PMA prevents this CD8-mediated death. In this proposal we will determine the pathway of apoptosis used by CD8-mediated apoptosis, determine the signaling events downstream of CD8 cross-linking that activate the apoptotic pathway, and determine if the physiological ligand for CD8, MHC class I molecules, can induce death in immature thymocytes. The results from the experiments outlined in this proposal will identify a new pathway leading to apoptosis.